Principal Investigator Contact Information

OVERALL ABSTRACT

The primary goal of The Ohio State University / M.D. Anderson Thyroid Cancer SPORE is to improve the outcomes and lives of patients with thyroid cancer by identifying genetically “at-risk” individuals allowing for early diagnosis and prediction of tumor behavior, developing new approaches to minimize side effects of treatments, and developing better biomarkers and treatment options for progressive metastatic disease. Several factors support the importance of applying these efforts to thyroid cancer: (1) Thyroid cancer incidence is rising at the fastest rate of all malignancies in the United States and worldwide; it is now the 5th most common malignancy in women and 11th most common in men. (2) Thyroid cancer typically takes an indolent course when patients are diagnosed early, thus with the increasing incidence there is an ever enlarging population of individuals (~600,000) surviving long term, many of whom suffer from lifelong effects of initial therapy. (3) For patients with more aggressive forms of thyroid cancer, such as medullary cancer (MTC), there exist no curative therapies or biomarkers that accurately predict death from disease or response to particular treatments thereby limiting efforts to individualize therapeutic intensity. In order to achieve our goals, this SPORE application proposed to support a multi-institutional team of experienced investigators from two of the leading institutions in the field with a history of collaborative clinical trials. We have chosen to focus on critical areas of need for rapid translation into clinical practice for thyroid cancer patients. Thus, if we are successful, the SPORE group will have impacted positively in thyroid cancer detection, treatment, management, and monitoring.

The goals of Project 1 are to advance the current knowledge of Papillary Thyroid Carcinoma (PTC) predisposition by determining the biological functions of identified risk mutations and determine if they predict thyroid cancer risk as well as tumor behavior. Investigators in Project 1 have published that several SNPs are highly associated with PTC, including two GWAS analyses using large patient populations with apparently sporadic disease. Candidate genes have been identified. A concept emerging is that long intergenic noncoding RNA genes (lincRNAs) are major players in thyroid cancer susceptibility, but the mechanisms involved need to be established. The goal will be to firmly identify genes that associate with PTC, determine the functions of these genetic changes, and determine if the genetic abnormality performs as a robust predictor of cancer risk and tumor behavior in patients with PTC.

The primary goal of Project 2 is to improve the quality of life of long-term thyroid cancer survivors by developing novel approaches to eliminate or reduce salivary gland damage from radioactive iodine therapy. Patients diagnosed with thyroid cancer often enjoy long-term survivorship. One of the common therapies employed is I-131. Unfortunately, I-131 treatment causes permanent salivary gland damage in as many as 30% of treated patients causing lifelong pain, dry mouth, taste disturbances, and dental damage. It is now recognized that the previous standard preventive measures may worsen this side effect. By case–control and prospective studies, Project 2 will determine the best strategies for predicting and preventing this complication, develop and test new biomarkers that predict a likelihood of salivary gland dysfunction, and develop new therapies to prevent this important survivorship issue.

The overall goal of Project 3 is to improve treatments for patients with progressive medullary thyroid cancer (MTC).MTC metastasizes earlier than other forms of differentiated thyroid cancer and accounts for a disproportionate amount of disease-related mortality. Treatment with multikinase inhibitors (MKI) induces stable disease or non-durable partial remissions in ~50% of patients. Recently, vandetanib and cabozantinib received FDA approval for treating patients with metastatic progressive MTC. However, patients require lifelong treatment and acquire resistance, creating the critical need for new second line therapies. The goal of Project 3 is to identify strategies to treat patients with resistant MTC. A focused Phase II clinical trial will be performed based on an observed synergy of targeting RET, RAF, and MEK. Additional studies will identify pathways of resistance using state-of-the-art genetic and proteomic approaches. A third approach will be to target cyclin-dependent kinases, which play a role in MTC development and progression in vivo.

The goal of Project 4 is to develop new biomarkers to assess medullary thyroid cancer progression, drug resistance, and early recurrence. The early identification of distant metastases and understanding the biological properties of metastasizing cells remain a challenge in MTC. Project 4 seeks to test several approaches to enhance detection of MTC progression using cell free DNA assays and circulating tumor cell (CTC) detection. The proposal builds upon the discovery of a MTC cancer stem cell subpopulation and the identification of cell-specific transcripts (PROM1, NKX2.2. and SOX2), that are upregulated by vandetanib treatment.

CORES

The work in the SPORE is supported by three outstanding cores with involvement at both institutions dedicated to supporting research at both SPORE locations and integrating efforts between OSUCCC and MDACC.

CORE A: INTEGRATED CLINICOPATHOLOGY and BIOREPOSITORY CORE

This Shared Resource Core is required by the SPORE as a Biospecimen and Biorepository Core. However, we have also chosen to incorporate clinical expertise into the Core under the leadership of pathology experts at both institutions, Dr. Adel El-Naggar and Dr. Paul Wakely, Jr. We believe that this innovative approach to fully integrate pathology and laboratory samples with clinical information and databasing is crucial to allow for maximal core impact on the Projects and on thyroid cancer research. It is the strong belief of the SPORE that upfront collection of detailed clinical information as allowed by IRB-approved protocols is essential to facilitate translational research. This principle has been utilized by our groups and we believe this maximally allows for rapid translation of research into the clinic.

Core B: Biostatistics Core

Core Leader:
Soledad Fernandez, PhD

Core B will provide biostatistical and bioinformatics analysis support to each of the projects as well as to investigators selected for the Developmental Researchor Career DevelopmentProjects. The approach of this Core has been to be involved in the experimental design of both laboratory and clinical studies to ensure robust and rigorous initial study design to appropriately test hypotheses. Dr. Fernandez is the Director of the OSUCCC Shared Biostatistical Resource and leads a team of statisticians who bring skills for specific types of analyses to the group. Our approach has not been to include individual biostatisticians in each Project, but rather to have the core provide these services and support personnel for this critical work. It is our philosophy that full integration and consistency in analysis is essential to the overall success of the SPORE, therefore all statistical analyses in all Projects at both sites will be performed with Dr. Fernandez and her group at OSU.

Core C: Administrative Core

Core Co-Leaders:
Matthew D. Ringel M.D.
Gilbert Cote, PhD

Core C will serve a primary integrative role for the SPORE with a goal to facilitate the success of each individual Project in all components. The Director of the Administrative Core, Dr. Ringel, has extensive experience in this area from other multicenter grant leadership roles.Dr. Gilbert Cotewill serve as the lead for the Administrative Core at MDACC.The Core will arrange an annual meeting of SPORE investigators to facilitate scientific exchange, component review, investigator interactions, and progress review. This meeting will include the internal and external SPORE Advisory Boards and will lead to creation of annual progress reports to the NCI as well as the participating institutions. Core C will assist with budget reviews and analysis to ensure efficient and appropriate use of funds, and will organize and maintain a secured website and arrange regular multi-site teleconferences and web-based presentations. The Core will also assist the Developmental Research and Career Development Programs (see below). In addition, the core will facilitate interactions between Project Co-Leaders as well as Core Co-Directors at both participating institutions. This will include physical meetings between the Core Director and Project and Core Co-Leaders at both OSUCCC and MDACC. Core C will function with the existing structures at both OSUCCC and MDACC but will focus on SPORE-specific issues that are beyond the scope of the general Shared Resource Cores at the two institutions including supporting and encouraging inter-SPORE collaborations.

Developmental Research Program (DRP)

Program Leaders:
Sissy Jhiang, PhD
Steven Sherman, MD

The DRP will be led by a primary Leader at OSUCCC along with a Co-Leader at MDACC. The OSUCCC Leader, Dr. Sissy Jhiang, is a well-established NIH funded laboratory investigator in thyroid cancer; the MDACC Co-Leader Dr. Steven Sherman is an international leader in thyroid cancer clinical trials. This model allows for stewardship of translational and clinical research projects. The goal of the DRP is to promote new translational research ideas in thyroid cancer and support them to attain independent funding or attain full project designation in the SPORE over time. There is also an important goal to attract established investigators from other areas of research into thyroid cancer translational research as there is a need for innovative approaches to research in this disease.

Career Development Program (CDP)

Program Leaders:
Lawrence Kirschner, MD, PhD
Robert Gagel, MD

The CDP is led by two senior translational researchers who have demonstrated major commitments to academic education and mentorship in leadership positions within their home institutions. Dr. Lawrence Kirschner, the CDP Leader at OSU, is the Associate Director of the MD, PhD Program at Ohio State, and is the past Director of the Endocrinology Fellowship, and has served on the Department of Internal Medicine Internship, College of Medicine Curriculum Development Committee, and Institutional Graduate Medical Education committee. The Co-Leader at MDACC, Dr. Robert Gagel, is currently the Head of the Division of Internal Medicine and prior to that as the Chairman of the Endocrine Department at MDACC. He has mentored a large number of young postdoctoral researchers, clinical fellows, and young faculty members. Both of these individuals are committed to recruiting and supporting new investigators to enter thyroid cancer translational research as well as supporting established investigators from other areas interested in moving into the thyroid cancer field. Both are experienced grant reviewers and effectively have administered large programs within their own institutions, thus both are highly qualified leaders for the CDP. There will be interaction and involvement with CTSA programs at both institutions, which provide additional training for grant writing and provide lectures and materials for young faculty members.